DESCRIPTION: Injury to major peripheral nerves can result in significant and long term functional deficits. The management of these injuries continues to be a significant problem for the reconstructive surgeon as the number of expendable cutaneous nerves that can be used as autografts is limited. The use of nerve graft material of allogenic origin would avoid the concomitant morbidity (scar, numbness or neuroma formation) associated with harvesting nerve autografts and offers a limitless source of nerve graft material to reconstruct large, multiple, and complex nerve injuries. Establishment of clinically applicable strategies for nerve allograft transplantation is a long term objective which would offer significant improved options for surgical reconstruction of traumatic peripheral nerve injuries. Previous work from this laboratory has demonstrated successful nerve allograft regeneration under the influence of Cyclosporin A (CsA) immunosuppression as well as the feasibility of nerve allograft preservation. Cold preservation (4 degrees C) for greater than one week reduced lymphocyte migration into the allograft significantly to levels below corresponding autograft levels. Specific aims of this study are to define the minimum preservation time that would decrease allograft immunogenicity and investigate the merits of a combination of graft preservation with short course CsA therapy.Achievement of these specific aims would have immediate impact on clinical nerve allotransplantation. Recent studies have demonstrated the potential efficacy of monoclonal antibodies (MAbs) against ICAM-1 and LFA-1 to suppress the nerve allograft response. Specific aims will address the potential of these Mabs in combination with preservation and CsA immunosuppression to significantly enhance allograft regeneration. The mechanism by which MAbs induce tolerance will be explored. Several animal models have been established to accomplish these specific aims. An ovine model of lymphocyte trafficking has been established to assess lymphocyte migration into the nerve allograft. A rodent model of nerve allograft rejection will be used to study the efficacy of short-course CsA therapy in combination with optimal nerve preservation parameters; in a limited number of primates these results will be confirmed in order to facilitate application toward human clinical trials. The rodent model will also be used to examine the mechanism of MAb induced adult peripheral tolerance. Assessment techniques will include T-lymphocyte cytotoxicity assays in combination with histological, morphological, electrophysiological, and functional assessment of nerve regeneration. Establishment of a nerve bank and the facilitation of clinic nerve transplantation is the broad objective of this proposal.